To date, seven compounds have been studied for transfer into milk which differ in lipid/water solubility, protein binding, and pKa. Di(2-ethylhexyl) phthalate (DEHP), a highly soluble, protein bound compound, was presented in high concentrations in rat milk, as expected. The H2-receptor anatagonists, cimetidine and ranitidine, are water soluble bases with low degrees of potential binding. In studies with rats, both drugs were found in higher concentrations in milk than in plasma, which would be expected due to the lower pH of milk. However, the milk/plasma ratio for cimetidine was much greater than would be predicted by ionic equilibrium, but was consistent with human data showing elevated milk/plasma ratio. Therefore, using the rat as a model, the mechanism of the elevated milk/plasma ratio for cimetidine was investigated. There was no evidence for increased protein binding in milk over that in plasma: no evidence or active or facilitated transport by mammary slices: and no evidence that cimetidine-induced prolactinemia as the cause of the high excretion into milk. Therefore, reasons for the high milk/plasma ratio are still unknown. We are currently further investigating the possibility that mammary secretory cells can actively-transport selected xenobiotics into milk.